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J. Biol. Chem., Vol. 280, Issue 13, 12956-12966, April 1, 2005

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Tal1/SCL Binding to Pericentromeric DNA Represses Transcription^*

Jie Wen, Suming Huang, Svetlana D. Pack¶, Xiaobing Yu||, Stephen J. Brandt**, and Constance Tom Noguchi

From the Molecular Medicine Branch and Laboratory of Molecular Biology, NIDDK and the ^¶Surgical Neurology Branch, NINDS, National Institutes of Health, Bethesda, Maryland 20892 and the ^**Departments of Medicine, Cell and Developmental Biology, and Cancer Biology, Vanderbilt University Medical Center and the Tennessee Valley Veterans Affairs Healthcare System, Nashville, Tennessee 37232

Tal1/SCL is a basic helix-loop-helix transcription factor critical for normal hematopoiesis. To understand the mechanisms underlying transcriptional regulation by Tal1/SCL, we combined an in vitro DNA binding strategy and an in vivo chromatin immunoprecipitation analysis to search for Tal1/SCL target regions in K562 erythroleukemia cells. A 0.4-kb genomic DNA clone containing two Tal1/SCL binding E-boxes and GATA- and SATB1-binding motifs (EEGS) was identified that localized to the pericentromeric region with high homology to satellite 2 DNA. Pericentric DNA is related to heterochromatin and gene inactivation. We found that Tal1/SCL could complex with the histone H3 lysine 9 (H3K9)-specific methyltransferase Suv39H1. Binding of Tal1/SCL to EEGS chromatin correlated with hypermethylation of H3K9 and the association of heterochromatin protein HP1 to this region. In Rep4 reporter gene assays, EEGS affected repression in a manner dependent on the expression level of Tal1/SCL that was accompanied by increased H3K9 methylation in chromatin associated with EEGS and a linked promoter. A specific histone deacetylase inhibitor, trichostatin A, relieved Tal1/SCL-mediated repression by EEGS. In addition, SATB1 bound EEGS chromatin and promoted Tal1/SCL EEGS-dependent repression. We expand the list of potential interacting partners for Tal1/SCL by demonstrating direct associations of Tal1/SCL with SATB1 and with Suv39H1. These results reveal a novel mechanism of action for Tal1/SCL and implicate heterochromatin-like silencing via a cis-acting binding motif for transcriptional repression.

Received for publication, November 10, 2004 , and in revised form, January 26, 2005.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| Present address: Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205.

To whom correspondence should be addressed: Molecular Medicine Branch, NIDDK, National Institutes of Health, Bldg. 10, Rm. 9N307, 10 Center Dr., MSC 1822, Bethesda, MD 20892-1822. Tel.: 301-496-1163; Fax: 301-402-0101; E-mail: cnoguchi{at}helix.nih.gov.

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